Association of Inferior Vena Cava Filter Placement for Venous Thromboembolic Disease and a Contraindication to Anticoagulation With 30-Day Mortality

IMPORTANCE Despite the absence of data from randomized clinical trials, professional societies recommend inferior vena cava (IVC) filters for patients with venous thromboembolic disease (VTE) and a contraindication to anticoagulation therapy. Prior observational studies of IVC filters have suggested a mortality benefit associated with IVC filter insertion but have often failed to adjust for immortal time bias, which is the time before IVC filter insertion, during which death can only occur in the control group. OBJECTIVE To determine the association of IVC filter placement with 30-day mortality after adjustment for immortal time bias. DESIGN, SETTING, AND PARTICIPANTS This comparative effectiveness, retrospective cohort study used a population-based sample of hospitalized patients with VTE and a contraindication to anticoagulation using the State Inpatient Database and the State Emergency Department Database, partoftheHealthcareCostandUtilizationProjectoftheAgencyforHealthcareResearchandQuality, from hospitals in California (January 1, 2005, to December 31, 2011), Florida (January 1, 2005, to December 31, 2013), and New York (January 1, 2005, to December 31, 2012). Data analysis was conducted from September 15, 2015, to March 14, 2018.


Introduction
Venous thromboembolism (VTE), which includes both pulmonary embolism (PE) and deep vein thrombosis (DVT), is a significant cause of morbidity and mortality worldwide, with an incidence of 117 cases per 100 000 person-years 1 and a 1-year mortality for PE of at least 22% in patients with Medicare. 2eatment of patients with VTE is based on anticoagulation, but for many patients, this therapy is contraindicated owing to recent surgery or underlying coagulopathies.In patients with VTE and a contraindication to anticoagulation, major professional societies, including the American College of Chest Physicians, 3 American Heart Association, 4 Society of Interventional Radiology, 5,6 American College of Radiology, 7 and the British Committee for Standards in Haematology 8 recommend consideration of IVC filter placement.While IVC filters have been widely available since the 1960s, their use in the United States has steadily and dramatically increased from 2000 procedures in 1979 to more than 100 000 procedures in 2005. 9More recently, rates have begun to decline with approximately 96 000 procedures in 2014. 10This use has occurred despite the absence of data on a mortality benefit associated with IVC filter placement.An early randomized clinical trial showed a reduction in the number of symptomatic PEs but no reduction in mortality after IVC filter insertion.Importantly, this trial excluded patients with a contraindication to anticoagulant therapy, 11 which is, to our knowledge, the most widely accepted indication for IVC filter placement and the only indication for which the several professional societies agree.Retrievable IVC filters were analyzed in a randomized clinical trial 12 of patients with PE and a high likelihood of recurrence.In this trial, 12 IVC filters did not lower recurrent PE, but patients with a contraindication to anticoagulation were excluded.Thus, the findings of existing randomized clinical trials are not applicable to a large segment of the VTE population.
As a result, in the last 3 years, observational studies have attempted to understand the association between IVC filter placement in patients with VTE and a contraindication to anticoagulation and their outcomes.These studies have often failed to adjust for immortal time bias, which is the interval between hospital admission and IVC filter placement, during which time death cannot occur in the intervention group but can occur in the control group. 13Failing to account for this potential source of bias can erroneously skew the results in favor of the intervention by falsely conferring a survival advantage to the treated group. 13Given this concern for unaccounted biases in the context of a relatively common invasive procedure for which there is no evidence of a mortality benefit, we conducted an analysis incorporating adjustment for immortal time bias using 2 different statistical models to evaluate the outcomes of IVC filter placement in patients with VTE and a contraindication to anticoagulation.to December 31, 2012). 14,15This study conformed to the International Society for

Primary Exposure, Outcomes, and Other Baseline Characteristics
During the index hospitalization, IVC filter insertion was identified by the ICD-9-CM procedure code 38.7.Comorbidities were identified using the Elixhauser classification 16 derived from the index hospitalization and admissions within the preceding year.Medical insurance (Medicare, Medicaid, private insurance, and other) and admission through the emergency department were identified at the index hospitalization.

Statistical Analysis
Our primary method of analysis was a multivariable Cox model with IVC filter status as a timedependent variable to account for immortal time bias.The start time for this analysis was the date of index hospitalization.Patients were followed up until the time of an event or censored at 30 days.
Patients with IVC filters were not identified until the time of procedure to allow for a time-dependent

Results
We identified 132 355 patients 18 years and older with an ICD-9-CM hospitalization code for PE, DVT, or both along with a contraindication to anticoagulation from California (2006-2010)

Discussion
The most significant finding of this study of IVC filter use in patients with VTE and a contraindication to anticoagulation is that treatment with an IVC filter was associated with a higher 30-day mortality than treatment without IVC filter placement after adjustment for demographics, comorbidities, immortal times bias, and the propensity to receive a filter.
The initial long-term evaluation of IVC filter use was by Greenfield et al in 1981 17 and was expanded in the late 1980s 18 to include 469 patients.This study showed a 4% rate of PE in patients after placement of an IVC filter but had suboptimal follow-up and lacked a control group.Largely based on this work, IVC filter implantation increased from 2000 procedures in 1979 to more than 100 000 in 2005. 9At present, there are 2 randomized clinical trials evaluating the long-term outcomes of IVC filter use.The first, originally published in 1998 11 with a follow-up report in 2005, 19 found that patients with VTE who were randomized to receive IVC filters experienced a reduction in symptomatic PE, no change in mortality, and an increased risk of recurrent DVT.Importantly, this trial excluded patients with a contraindication to anticoagulation, negating its applicability to the subset of patients in whom IVC filters are most universally recommended.The second study, 12 published in 2015, randomized 399 patients with PE and a high probability of recurrence to anticoagulation and a retrievable IVC filter vs anticoagulation alone.The outcomes of the 2 groups did not differ with respect to the primary outcome of recurrent PE or secondary outcomes including death or DVT at 3  Given the widespread use of IVC filters and persistent questions regarding their efficacy, several observational studies within the last 5 years have attempted to further evaluate the association of IVC filter use and mortality.

Limitations
Our findings should be interpreted within the context of several limitations.This study is retrospective and uses observational data derived from codes designed for reimbursement.A 2016 study proposed that the use of diagnostic codes from claims data can lead to an underestimation of event rates. 24Furthermore, retrospective observational studies may be subject to various types of bias that persist despite various techniques to adjust for differences in baseline characteristics.
Therefore, these results should be considered hypothesis generating only.Second, this study only captured patient deaths during the index hospitalization, on a repeated admission or at a subsequent emergency department visit in the same state as the index hospitalization, thereby allowing for the possibility that some out-of-hospital or out-of-state deaths were not captured.However, there is no reason to believe these uncaptured events would occur more frequently in one group than in the other.Third, contraindications to anticoagulation span a range from minor relative contraindications to severe absolute contraindications.The lack of granularity of administrative data precludes the determination of the degree of absoluteness of any patient's contraindication to anticoagulation, whether therapeutic anticoagulation was attempted but required discontinuation, or if a patient was This comparative effectiveness, retrospective cohort study used the State Inpatient Database (SID) and the State Emergency Department Database, a part of the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, from hospitals in California (January 1, 2005, to December 31, 2011), Florida (January 1, 2005, to December 31, 2013), and New York (January 1, 2005, Pharmacoeconomics and Outcomes Research (ISPOR) reporting guideline.The SID includes inpatient discharge records from nonfederal, short-term general hospitals.The SID data sets from California, Florida, and New York contain an encrypted person identifier allowing longitudinal follow-up.Records with a missing person identifier and records from psychiatric, dependency, and rehabilitation hospitals were excluded.Same-day hospital transfers were considered a single hospitalization.Each SID record contains International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis and procedure codes.Diagnosis codes are assigned at discharge without corresponding timing information and include 1 primary admitting diagnosis code that reflects the principle reason for hospitalization.Each procedure code has corresponding timing information indicating the day of the procedure during the hospitalization.The State Emergency Department Database includes records for JAMA Network Open | Cardiology

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-affiliated emergency department visits not resulting in hospitalization.Emergency department visits resulting in hospitalization are included in the SID.The Washington University Human Research Protection Office granted this study an exemption from institutional review board oversight due to the deidentified nature of the data set.

Table 1 .
ICD-9-CM Diagnosis and Procedure Codes Used to Identify Study Conditions and Procedures filter status.The following variables were used in the multivariable, time-dependent Cox model and to build a propensity score with a logistic regression model: age, sex, primary payer, admission through emergency department, thromboembolism, intracranial bleeding, other major bleeding, thrombocytopenia, active gastrointestinal ulcer, hemophilia or von Willebrand disease, cerebral aneurysm, aortic dissection, pericardial disease, bacterial endocarditis, preeclampsia and eclampsia, malignant hypertension, brain surgery, spinal surgery, eye surgery, congestive heart failure, valvular disease, pulmonary circulation disease, peripheral vascular disease, paralysis, other neurologic disorders, chronic obstructive pulmonary disease, diabetes, hypertension, hypothyroidism, renal failure, liver disease, peptic ulcer disease, lymphoma, metastatic cancer, solid tumors without metastasis, rheumatoid arthritis, coagulopathy, obesity, weight loss, fluid and electrolyte disorders, chronic blood loss anemia, alcohol abuse, drug abuse, psychoses, and depression.A second Cox model was created that included the original variables and the propensity score as an additional adjustment variable.The follow-up period started at the admission date of the index hospitalization for individuals with and without IVC filter insertion.The primary outcome of interest was mortality at 30 days.Baseline characteristics of patients with and without IVC filter were compared using 2-sample t test for continuous variables and χ 2 test for categorical data.To account for any overdispersion, the Pearson χ 2 test was used to adjust standard errors via quasi-likelihood estimation.A 2-sided t test was used, and P < .05 was considered statistically significant.All analyses were conducted using SAS, version 9.3 and SAS Enterprise Guide, version 7.1 (SAS Institute Inc).JAMA Network Open.2018;1(3):e180452.doi:10.1001/jamanetworkopen.2018.0452July 13, 2018 3/9 Downloaded From: https://jamanetwork.com/ on 09/17/2023 Abbreviation: ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.
, Florida (2006-2012), and New York (2006-2011).After application of exclusion criteria, 126 124 patients remained in the study.Of these, 94 patients with IVC filter had incomplete data for analysis, leaving 126 030 patients in the final study population (Figure), with 45 771 (36.3%) receiving an IVC filter

Table 2 .
Patient Characteristics Because both groups had anticoagulation, patients with a contraindication to anticoagulation were excluded.In contrast, our study evaluates a diverse patient population with multiple contraindications to anticoagulation and not only extends the findings of prior IVC filter publications but also adjusts for the effect of immortal time in observational studies to bias results in favor of intervention.